Octanol−, Chloroform−, and Propylene Glycol Dipelargonat−Water Partitioning of Morphine-6-glucuronide and Other Related Opiates

Avdeef, Alex; Barrett, David A.; Shaw, P. Nicholas; Knaggs, Roger; Ss, Davis

doi:10.1021/jm960073m

Cited by 86 publications

(60 citation statements)

References 22 publications

(57 reference statements)

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“…After retrodialysis and washout with blank perfusate, the drug was administered intravenously as a bolus dose plus a 4-h constant rate infusion to obtain steady state. The size of the bolus Avdeef et al, 1996. dose and the infusion rate were adjusted according to the plasma pharmacokinetics. CP-122721 was dissolved in saline.…”

Section: Methodsmentioning

confidence: 99%

In Vitro Methods for Estimating Unbound Drug Concentrations in the Brain Interstitial and Intracellular Fluids

Fridén¹,

Gupta²,

Antonsson³

et al. 2007

Drug Metab Dispos

176

190

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ABSTRACT:Concentrations of unbound drug in the interstitial fluid of the brain are not rapidly measured in vivo. Therefore, measurement of total drug levels, i.e., the amount of drug per gram of brain, has been a common but unheplful practice in drug discovery programs relating to central drug effects. This study was designed to evaluate in vitro techniques for faster estimation of unbound drug concentrations. The parameter that relates the total drug level and the unbound interstitial fluid concentration is the unbound volume of distribution in the brain (V u,brain ). It was measured in vitro for 15 drugs using brain slice uptake and brain homogenate binding methods. The results were validated in vivo by comparison with V u,brain microdialysis results. The slice method results were within a 3-fold range of the in vivo results for all but one compound, suggesting that this method could be used in combination with total drug levels to estimate unbound interstitial fluid concentrations within reasonable limits. Although successful in 10 of 15 cases, the brain homogenate binding method failed to estimate the V u,brain of drugs that reside predominantly in the interstitial space or compounds that are accumulated intracellularly. Use of the simple methods described in this article will 1) allow quantification of active transport at the blood-brain barrier in vivo, 2) facilitate the establishment of a relationship between in vitro potency and in vivo activity for compounds acting on central nervous system targets, and 3) provide information on intracellular concentrations of unbound drug.

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Section: Methodsmentioning

confidence: 99%

In Vitro Methods for Estimating Unbound Drug Concentrations in the Brain Interstitial and Intracellular Fluids

Fridén¹,

Gupta²,

Antonsson³

et al. 2007

Drug Metab Dispos

176

190

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“…In rats, the transfer half life, again in an analgesia model, was estimated at 1.4 hr. 53 The lower permeability of the BBB to M6G compared with morphine is believed to be associated with the lower lipid solubility of M6G, 24,158 although this may be mitigated to some extent by the ''molecular chameleon'' nature of M6G with reduced surface charge caused by folding of the molecule. 159,160 M6G is considered generally to cross the BBB by diffusion.…”

Section: Brain Penetrationmentioning

confidence: 99%

Morphine‐6‐glucuronide: Actions and mechanisms

Kilpatrick¹,

Smith²

2005

Medicinal Research Reviews

128

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Morphine-6-glucuronide (M6G) appears to show equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression. The purpose of this review is to examine the evidence behind this statement and to identify the possible reasons that may contribute to the profile of M6G. The vast majority of available data supports the notion that both M6G and morphine mediate their effects by activating the micro-opioid receptor. The differences for which there is a reasonable consensus in the literature can be summarized as: (1) Morphine has a slightly higher affinity for the micro-opioid receptor than M6G, (2) M6G shows a slightly higher efficacy at the micro-opioid receptor, (3) M6G has a lower affinity for the kappa-opioid receptor than morphine, and (4) M6G has a very different absorption, distribution, metabolism, and excretion (ADME) profile from morphine. However, none of these are adequate alone to explain the clinical differences between M6G and morphine. The ADME differences are perhaps most likely to explain some of the differences but seem unlikely to be the whole story. Further work is required to examine further the profile of M6G, notably whether M6G penetrates differentially to areas of the brain involved in pain and those involved in nausea, vomiting, and respiratory control or whether micro-opioid receptors in these brain areas differ in either their regulation or pharmacology.

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“…For example, at an ionic strength of 0.001 M, morphine's pKa values were determined to be 8.13 ± 0.01 and 9.46 ± 0.01, whereas at ionic strengths of 0.15 M morphine pKa values were determined to be 8.17 ± 0.01 and 9.26 ± 0.01 at 25 C [173,174]. The varying ionic strengths were likened to low salt content and high salt content of food.…”

Section: Numerous Other In-vitromentioning

confidence: 99%

Drug release from matrix tablets: physiological parameters and the effect of food

Nokhodchi

Asare-Addo

2014

Expert Opinion on Drug Delivery

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Introduction: As dissolution plays an important and vital role in the drug-delivery process of oral solid dosage forms, it is, therefore, essential to critically evaluate the parameters that can affect this process. Areas covered:The consumption of food as well as the physiological environment and properties of the gastrointestinal tract, such as its volume and composition of fluid, the fluid hydrodynamics, properties of the intestinal membrane, drug dose and solubility, pK a , diffusion coefficient, permeability and particle size, all affect drug dissolution and absorption rate. There are several dissolution approaches that have been developed to address the conditions as experienced in the in vivo environment, as the traditional dissolution being a quality control method is not biorelevant and as such do not always produce meaningful data. This review also describes the development of a systematic way that differentiates between robust and non-robust formulations by varying the effects of agitation and ionic strength through the use of the automated United States Pharmacopeia type III Bio-Dis apparatus. Expert opinion:With the improved understanding of the physiological parameters that can affect the oral bioperformance of dosage forms, strides have, therefore, been made in making dissolution testing methods more bio-logically based with the view of obtaining more in vitro--in vivo correlations.Keywords: agitation rate, biodissolution, drug release, effect of food, hydrophilic matrices, ionic strength Highlights -Understanding all the physiological parameters can serve as a basis for designing dissolution testing methods and systems that can more fully represent the gastrointestinal (GI) tract in humans and allow more in vitro-in vivo (IVIVC) correlations to be obtained thereby improving the oral bioperformance of dosage forms.-Simulation of GI conditions is essential to adequately predict the in vivo behaviour of drug formulations.-The choice of appropriate media for in vitro tests is crucial to their ability to correctly forecast the food effect in pharmacokinetic studies.-Several methods of dissolution testing have been conducted and are still ongoing that seek to further understand and develop media and dissolution methods to better represent the in vivo conditions and to aid in the better prediction of in vivo drug release.-Systematic change of agitation method and ionic strength evaluation may be used as additional tools in allowing for the identification of potential fed and fasted effects on drug release from hydrophilic matrices in the drive for developing dissolution methodologies that are more relevant in helping to achieve more IVIVC.

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Octanol−, Chloroform−, and Propylene Glycol Dipelargonat−Water Partitioning of Morphine-6-glucuronide and Other Related Opiates

Cited by 86 publications

References 22 publications

In Vitro Methods for Estimating Unbound Drug Concentrations in the Brain Interstitial and Intracellular Fluids

In Vitro Methods for Estimating Unbound Drug Concentrations in the Brain Interstitial and Intracellular Fluids

Morphine‐6‐glucuronide: Actions and mechanisms

Drug release from matrix tablets: physiological parameters and the effect of food

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